In the past two decades, tremendous advances have been made in understanding the molecular mechanisms used by various types of cell surface receptors to transduce signals. Nearly all of these advances have come from the study of model systems where a receptor “activates” cells to generate a well-defined response. As knowledge about activating model systems has increased, it has become clear that there are many situations in which the activating signal sent from one receptor is modulated as the direct result of a negative or inhibitory signal sent by another cell surface receptor. While the study of this type of signaling is generally in its infancy, several recent studies have begun to shed light on the molecular mechanisms which underlie receptor-mediated inhibitory signals in immunologic systems. Given the tendency of nature to utilize signaling functions modularly in a variety of signaling pathways, the paradigms outlined by these systems may have implications for the study of inhibitory or deactivating signals in non-immunologic situations as well. In addition, the study of these signals may add new dimensions to the understanding of other widely utilized signaling pathways.